·To describe arteriolar calibre, vascular resistance, the measurement of arterial blood
pressure and the pressures of the pulmonary system, the role of myoglobin,
respiratory arrhythmia, alterations of mean arterial pressure and pressure
amplitude.

·To calculate one variable when relevant variables are given.

·To explain the control of the arterial pressure, hypertension, and reactive hyperaemia.

·The
haemodynamic features of the cardiovascular system are determined by Newtonian
and non-Newtonian relations between the driving blood pressure, the bloodflow
and the vascular resistance.

·These
features are related to the ability of each tissue to control its own
bloodflow in accordance with its needs. The control of local vascular
resistance is a combination of neural and metabolic factors affecting a basal
smooth muscle tone.

·Arterioles are vessels that range from 150 to 10 mm
in diameter. They control the distribution of blood to different tissues.

·Arteriolar
calibre is the internal
diameter of the arteriole, and the size is determined by the contractile
activity of its smooth muscle cells and by the transmural arteriolar pressure.

·Autoregulation is an automatic control phenomenon that aims at maintaining a constant
bloodflow when the driving pressure is changed.

·Capillary
intermittence: Krogh presumed
that a tissue capillary shifts between a closed and an open state. The
capillary diameter varies with the oxygen tension. In well-perfused tissue,
high O2 tension causes vasoconstriction and thus tends to reduce
its perfusion.

·Inflammatory
hyperaemia refers to
increased bloodflow with accumulation of leucocytes. This reaction is mainly
caused by leukotrienes released by the leucocytes.

·Malignant
hypertension (accelerated)
refers to a rapid and serious rise of the arterial blood pressure. The
condition can start as paralysis, unconsciousness, or blindness.

·Metabolic
control is the sum of all
metabolic factors that match the oxygen supply to the energy requirement.

·Myoglobin is a red, iron-containing, oxygen-binding globin similar to haemoglobin.

·Reactive
hyperaemia is the increase in
bloodflow following temporal vascular interruption of surgical or experimental
character.

·Standard
affinity of myoglobin towards
O2 is the reaction rate at 50% binding. This standard affinity is
much higher than that of haemoglobin towards oxygen.

·Secondary
hyperaldosteronism is
recognised by high serum concentrations of renin and aldosterone. This occurs
in malignant hypertension or following prolonged use of diuretics. The
patients develop cerebral oedema and haemorrhage, cardiac failure and
hypertensive nephropathy with proteinuria and microscopic haematuria.

·Systemic
hypertension -
according to WHO - is defined as an arterial blood pressure exceeding 160/95
mmHg (21.3/12.6 kPa) for several months. The pressure increase is either
systolic, diastolic or a combination.

·Systemic
resistance is the total
peripheral vascular resistance (TPVR),
mainly consisting of the arteriolar resistance (in particular that of the
essential arterioles in the large striated muscles).

·Vasomotion is the rhythmic changes in the arteriolar diameter that causes bloodflow
to fluctuate. Vasomotion is brought about by active changes in the tension of
vascular smooth muscles. The arteriole can relax completely and then close
completely.

·Vasopressin is another name for anti-diuretic
hormone (ADH) from the hypophyseal posterior lobe. ADH controls renal
water retention and acts as a moderate vasoconstrictor.

·VIP isVasoactive Intestinal Polypeptide from the intestine, the salivary
glands and the penile cavernous bodies. VIP is a neurotransmitter and a potent
vasodilatator, which is used in the treatment of impotence.

This paragraph deals with 1.
Autoregulation, 2. Autonomic nervous control, 3. The baroreceptors and other
regulators, 4. Oxygen release to the mitochondria, 5. Measurement of blood
pressure, 6. Age and MAP.

The resistance vessels of the coronary system tend to diminish any change in the bloodflow in the coronary vessels that are triggered by
changes in the driving pressure within a certain range. Increases or
reductions in the driving pressure are immediately followed by similar
alterations of coronary bloodflow. However, the resistance of the vessels is
then changed - metabolically and mechanically - so that the final coronary bloodflow is maintained at control levels at all times (changes
along the arrows in Fig. 9-1).

Autoregulation has
been explained by at least two theories:

1) The myogenic theory considers autoregulation as a myogenic response- an intrinsic
property of vascular smooth muscle. Increased stretch of the smooth muscle
elicits contraction, whereas diminished stretch elicits vasodilatation. This
is illustrated in Fig. 9-1, where an abrupt rise in perfusion pressure from
115 mmHg passively stretches the wall (increases the transmural pressure) and
produce an initial increase in bloodflow. Then the vascular smooth muscles
contract and the bloodflow falls along the arrows, so that the coronary
bloodflow is maintained at 200-250 ml min-1. Similarly, an abrupt
fall in perfusion pressure from 115 mmHg has the opposite effect, so the
normal bloodflow is re-established.

2) The metabolic control theory.

Fig.
9-1: Autoregulation: Changes in bloodflow triggered by changes of the
driving pressure has a tendency to be diminished. The example here is the
coronary bloodflow, which is described further in relation to Fig. 10-7.

Metabolic
control is the sum of all
metabolic factors that match the oxygen supply to the energy requirement.

There is a remarkable proportionality between changes of myocardial
oxygen consumption and coronary bloodflow. If the oxygen supply is
insufficient compared to the myocardial demand, a vasodilatator is releases
from the myocytes to the interstitial fluid, so the coronary resistance
vessels dilatate.

Adenosine is continuously produced by breakdown of ATP. Adenosine is a likely candidate for the role of metabolic
mediator, because it is such a potent vasodilatator and because it
diffuses readily across the cell membranes. Adenosine may work via presynaptic
inhibition of sympathetic nerve fibres to the smooth muscles of the
coronary resistance vessels. Falling perfusion pressure leads to diminished
rate of adenosine washout and thus to local vasodilatation. Adenosine
dilatates the vessels and causes increased coronary bloodflow. Increased
perfusion pressure washes out adenosine, which leads to vasoconstriction and
local decrease in bloodflow until it is re-established. - The myogenic and the
metabolic control frequently co-operate during autoregulation.

The sympathetic and the parasympathetic division of the autonomic nervous
system control the tone of the resistance vessels by opposing actions. Almost
all blood vessels receive efferent nerve fibres from the sympathetic nerve system to their smooth muscles.

True capillaries do not contain smooth muscles and do not receive
autonomic nerve supply. Metarterioles and capillary sphincters do not receive
nerve fibres at all.

The sympathetic vasoconstrictor fibres and circulating catecholamines
control both arteriolar, venous and venule tone. The vessels are innervated by
postganglionic neurons from the paravertebral sympathetic trunk. The
noradrenergic control releases noradrenaline and ATP. The transmitter
transport is axonal. Noradrenaline binds to a-adrenergic
constricting receptors. Adrenaline binds to both a-adrenergic constricting receptors and to b-adrenergic dilatating receptors. Consequently,
adrenaline elicits vasoconstriction in arterioles where a-receptors predominate, and vasodilatation where b-adrenergic
receptors predominate. Adenosine dilatates vessels, because it inhibits
release of noradrenaline possibly via presynaptic purine receptors. In the
synapse, the neurotransmitter is eliminated by re-uptake, by enzymatic
breakdown and by diffusion. The arterioles of the skeletal muscles, the skin,
the kidneys and the splancnic region are densely innervated.

Hunting
predators are claimed to have sympathetic vasodilatator fibres to the skeletal
muscle vessels, which is consequential during hunting, but such fibres have
not been found in humans (Uvnaes).

The
cholinergic system is almost exclusively parasympathetic.
The vessels of the head, neck and thoraco-abdominal organs receive
parasympathetic nerve fibres (the 3rd, 7th, 9th and 10th cranial nerves). The
large intestine, bladder and genital organs receive parasympathetic fibres
from the sacral segments 3-5. The nerve fibres to the external genitals are

active
during sexual excitation. Acetylcholine is the vasodilatating transmitter for
muscarinic and nicotinic cholinergic receptors. Purinergic receptors use
vasodilatating transmitters as ATP, AMP and the potent adenosine.

Rapid regulators of the arterial blood pressure are the arterial
baroreceptors originating from the carotid sinuses and the aortic arch.
These classical arterial pressor-receptors are well established and work
within seconds following dynamic changes in blood pressure. The arterial
baroreceptors probably do not regulate chronic blood pressure changes with
constant tone.

The baroreceptor reflex is triggered by stretch of the wall, and the
receptors are also called stretch receptors or pressor-receptors. The
baroreceptors are mainly located in the walls of the internal carotid arteries
(known as the carotid sinuses) and in the aortic arch. Signals are transferred
from each carotid sinus via afferent nerve fibres forming the sinus nerve to
the glossopharyngeal nerve, and conducted to the nucleus of the solitary tract
of the brain stem.

The impulse frequency in the nerve afferents increases with the arterial
pressure maintained over a period (Fig. 9-2). The curve is S-shaped with a
steep rise in the normal range of arterial pressures, indicating an optimal
sensitivity in this area. There is no activity below 60 mmHg.

An increasing rate of pressure change (dP/dt; a sudden rise in pulse
pressure amplitude) also increases the firing rate in a single nerve fibre
(Fig. 9-2, right). Thus, baroreceptors act as differential-sensors. The frequency during the rising systolic
pressure is distinctly greater than that in the diastole.

Fig. 9-2:
Activity in the carotid sinus nerve at maintained arterial pressure (left) and
during a single cardiac cycle with low, normal and high blood pressure.

The afferent signals are conducted to the nucleus of the solitary tract
in the medulla. This nucleus is the site confluence for both baroreceptor and
chemoreceptor signals. Stimulation here inhibits sympathetic structures and enhances parasympathetic structures.Thus,
a rise in arterial pressure causes vasodilatation and a fall in heart rate,
both of which contribute to a lowering of blood pressure.A primary fall in arterial pressure elicits vasoconstriction
and a rise in heart rate, both of which contribute to a rising blood pressure.

Change of body posture from lying to erect reduces the arterial pressure
in the carotid sinuses, which elicits an immediate reaction with strong
sympathetic tone and diminished vagal tone. This minimises the fall in brain
blood pressure, and prevents loss of consciousness. – Hypotensive drugs,
exposure to weightlessness, and immobilisation interfere with the baroreceptor
reflex, which normally protects us during standing. Such individuals may
develop orthostatic hypotension,
when they stand up and they may faint.

Behavioural and emotional control of blood pressure and heart rate is
exhibited by the hypothalamus. This
autonomic control centre also includes a temperature centre from where
contraction of skin vessels is instituted in cold environments.

In hypertension the baroreceptor system
adapts to the rising pressure within days by moving up the set point.Patients with hypertension have stiff arterial walls as a result of the
high arterial pressure, so their baroreceptors are less sensitive than in
healthy persons. The increased arterial stiffness is not the main phenomenon
in hypertension. Most hypertensive patients are dominated by increases
peripheral vascular resistance, which mainly affects the diastolic arterial
pressure.

Patients with hypersensitive baroreceptors in the carotid sinuses to external pressures are in danger of
hypotension with fainting and death from external pressure over the neck at
the site of the carotid sinus (so-called carotid
collar syncope or collar death). Tight collars
or other types of external pressures elicit fainting due to marked
vasodilatation and hypotension. - Another cause is emotional
fainting (vasovagal syncope) with a strong emotional activation of the
vagus tone via hypothalamus.

Three
types of regulators are
involved in the adjustment of blood pressure. They are classified as
short-term, intermediate-term and long-term regulators.

1.The arterial baroreceptor
reflexes described above operate rapidly.

2.Transcapillary
volume shifts in response to
changes in capillary blood pressure, begin their function within minutes. When
veins are stressed by increased pressure, they slowly expand so that the blood
pressure decreases. Conversely, when the intravascular volume decreases, the
opposite occurs.

3.Renal
regulation of the body fluid volume.

When arterial pressure rises,
more urine is excreted. Hereby, the plasma and interstitial volume is reduced.
The diminished plasma volume
decreases venous return to the heart, reducing cardiac output, so that
elevated arterial blood pressure is brought back towards normal (Fig.
9-6).

A decrease in arterial pressure elicits the opposite reaction: The renin-angiotensin-aldosterone-cascade is triggered (Chapter
24). Aldosterone from the adrenal cortex promotes Na+-reabsorption
and K+-secretion from the renal tubules. The reabsorbed Na+ augments water retention (Fig. 9-6), as does also increased vasopressin (ADH)
secretion from the posterior pituitary. A falling arterial pressure also
diminishes the release of atrial natriuretic peptide (ANP), and its Na+ -
and water- excreting actions are reduced (Fig. 9-6).

1.Myoglobin in muscle cells releases O2 during muscular contraction, when
the blood supply is blocked. Myoglobin is important as a dynamic O2 store in muscle cells, although myoglobin is not totally saturated with O2.
During muscular contraction the bloodflow is blocked, and the O2 tissue tension falls drastically. Myoglobin then gives off O2 to
the cell. The P50 for oxymyoglobin is only 5 mmHg (compare to 27
mmHg for oxyhaemoglobin). Bloodflow is re-established during muscular
relaxation. Thus, myoglobin is rapidly reloaded, even when there is only a small rise in O2 tension.

Oxygen is lipophilic. Since almost the entire capillary surface is identical to the lipid containing
plasma membrane of the endothelial cells, oxygen is able to use the total
capillary surface for diffusion. The transport of lipophilic molecules is perfusion limited.

Oxygen diffuses so easily over the capillary endothelium, that there is tension
equilibrium between blood and tissues already at the arterial capillary end.

With rising perfusion the tension equilibrium point is shifted towards
the venous part.

Due to the oxyhaemoglobin, the O2 tension can be maintained
through the entire capillary. The oxygen tension varies in the tissues. There
is a longitudinal tension drop towards the venous end of the capillary, and radial tensions drop in the
tissue itself. In brain tissue, the O2 tension can vary from an
arterial level in certain small areas (PaO2 of 13.3 kPa or 100 mmHg) towards zero, when bloodflow is insufficient.

Brain and heart tissues are extremely sensitive to a fall in PO2.

Brain tissue is found in the nerve cells of the retina. These nerve cells
are deprived of oxygen in 4.5 s (occurrence of black out). This can be verified by pressure on the upper eyelid.
Consciousness is lost (grey out) a
few seconds after cardiac arrest. After 90 s, the brain interstitial fluid [K+]
increases drastically from 3 to 60-70 mM, and both action potentials and
synapse transmissions are eliminated. There is ion equilibrium over the cell
membranes. Intracellular [Na+] also increases drastically and
intracellular brain oedema develops. A high extracellular [K+] is
life threatening.

The EEG of an anoxic brain is recognisable as a straight EEG trace(no
electrical activity) indicating brain death. Because [Ca2+] rises
in the nerve cell, this increases the K+ conductance, so that more
K+ leaks out into the interstitial fluid.

The kidneys only
use 15 ml O2 each min but they receive 25% of the cardiac output at
rest (1200 ml per min containing 200 ml O2 per l). The kidneys have
the lowest arteriovenous O2 content difference of all the larger
organs in our body. The large safety margin is important for this vital organ during bleeding or
when the renal bloodflow is reduced (more in Chapter
25).

The arterial blood pressure is measured indirectly in the brachial artery
with Korotkoff´s auscultatory method.
WHO has proposed standardisation of this method. Continuous intra-arterial
recordings can obtain exact arterial blood pressure measurements. Comparison
with intra-arterial recordings have shown that Korotkoff´s method estimates
the systolic pressure too low (about 10 mmHg), and the diastolic pressure
differs a few mmHg.

The blood pressure increases in some patients due to the presence of a
doctor (ie, white coat hypertension).
This is revealed by repeated measurements – preferably performed before,
during and following exercise.

Ejection of blood from the left ventricle triggers a pulse wave in the
wall of the arterial tree, and the volume-pressure variations here distribute
with a large velocity along the arterial tree. In young persons the velocity
is 5-10 m per s; with age, atherosclerosis and hypertension the arterial tree
becomes stiffer and the velocity increases (see Ch. 8 about compliance and
also Fig. 8-8).

Fig. 9-3: Changes in pressure in the arterial
tree of a supine healthy person.

The systolic pressure increases progressively along the arterial tree,
whereas the diastolic and the MAP decrease (Fig. 9-3). The pulse amplitude,
which is the difference between systolic and diastolic pressure therefore,
increases clearly (Fig. 9-3). The end of systole is marked by a brief sharp
fall in pressure (dicrotic notch), caused by the relaxation of the ventricle
with backflow of blood as the aortic valves close. This backflow pressure
moves with the blood all along the arterial tree (Fig. 9-3).

The blood pressure has to be measured repeatedly, with the patient
sitting comfortably in a relaxed environment, and measured at more than three
consultations in order to avoid false alarm with white coat hypertension. A
diastolic pressure above 95 mmHg (12.6 kPa) expresses an increased MAP and the
age of the patient influences the strategy of the treatment.

Fig. 9-4: Normal pressures in the circulation of
a supine healthy person.

Essential diurnal variations
are present, but repeated blood pressure measurements over three consultations
seem to define a reasonable diurnal mean level. Continuous recording of the
arterial pressure is sometimes necessary.

Patients below 40 years of age, with a diastolic pressure above 100 mmHg
must be followed and examined further. Patients above 40 years of age, with a
diastolic pressure above 120 mmHg, must be examined further.

Normal values for blood pressures measured in different locations of the
circulation are given in Fig. 9-4.

Populations living under natural
conditions - including Indian troops in Brazil and healthy living persons
in the Western Hemisphere - maintain their mean arterial pressure (MAP)
throughout life. Their distribution curve for MAP is close to the normal
distribution.

The MAP and the systolic pressure measured as an average for the total
population, increases with increasing age in the rich part of the World.

As an order of thumb, the systolic blood pressure in mmHg is equal to 100
plus age in years, because these values are close to typical statistical mean
values from examination of large population groups. This is because general
diseases, with consequences for the systolic blood pressure and MAP, are
accumulated with age in the Western Hemisphere. Quite a few of the accumulated
disorders (such as atherosclerosis – see Chapter
10) probably occur as a
consequence of our life style-
operating in a heterogeneous genetic pool.

Previously, systemic hypertension was therefore characterised by a MAP
larger than normal for the age. Practically difficult comparisons had to be
made with a statistical, so-called normal material. Today, most doctors use
the WHO definition (see below).

The MAP is a good estimate of the driving pressure, and the cardiac
output is the stroke volume multiplied by the cardiac frequency.MAP and cardiac output are easy to determine, so the TPVR can be calculated.

With pressure expressed in mmHg and cardiac output expressed in ml per s,
the unit for TPVR is 1 mmHg*s*ml-1.
This unit is complicated in writing and the abbreviation is 1 PRU (Pressure
Resistance Unit). The normal value for TPVR in the systemic circulation at rest is one PRU, and during exercise it is only
0.3 PRU.

Primary hypertension always has a diastolic element reflecting involvement of the resistance
vessels (eg, muscular arterioles etc). Secondary
hypertension, caused by atherosclerosis or other types of stiff arterial
walls, is often purely systolic.

In the early stages of hypertension, the arterial blood pressure is
oscillating between hypertensive episodes and normal periods. The hypertensive
episodes are typically dominated by sympathetic overactivity with increased
cardiac output and almost unchanged total
peripheral vascular resistance (TPVR). Eventually, the pressure changes
the distensibility of the arteriolar walls and thus leads to sustain
structural changes of the resistance system. As the hypertension develops the TPVR is increased.

Any rise in blood pressure is a strong stimulus to the high-pressure
baroreceptors, but these essential sensors do not always work appropriate in
hypertension. The expected bradycardia from the high arterial pressure acting
normally on the arterial baroreceptors is not seen in hypertensive patients.

The initial sympathetic tone is also depicted in the high resting heart
rate, in contrast to the bradycardia found normally, when the blood pressure
rises. The abnormal baroreceptor reflex is probably an adaptive consequence of
the variable but lasting initial hypertension.

Permanent structural changes of the resistance vessels, with strongly
reduced specific compliance (reduced distensibility) and reduced lumen of
arterioles and small muscular arteries, eventually leads to permanent
hypertension.

The rising TPVR implies a
rising workload for the left ventricle and thus creates left ventricular
hypertrophy.

The typical patient with hypertension is asymptomatic. This is what makes the development of this disorder
dangerous. The first sign of systemic hypertension is sometimes acute
myocardial infarction with sudden death. Of all acute cases of myocardial
infarction up to 25% only experience a sudden pain, there is cardiac arrest,
and the cases are recorded as sudden death from myocardial infarction at
section.

Malignant or accelerated
hypertension refers to a
rapid and serious rise of the arterial blood pressure. The condition can start
as paralysis, unconsciousness, or blindness.

Secondary hyperaldosteronism is
recognised by high serum concentrations of renin and aldosterone. This occurs
in malignant hypertension or
following prolonged use of diuretics. The patients develop cerebral oedema and
haemorrhage, cardiac failure and hypertensive nephropathy (with proteinuria
and microscopic haematuria). Patients with malignant hypertension develop dissecting aortic aneurysms and retinal
damage with papiloedema, so they die rapidly without specific therapy.

Ophtalmoscopy for hypertonic changes of the retina also provides the diagnosis hypertension.
These changes include haemorrhages in the retinal nerve fibre layer, exudates
as yellow-white spots called cotton wool
spots, irregular arteriolar diameter, microaneurysms, and papillary stasis
(Fig. 9-5).

Fig. 9-5:
Hypertonic changes of the retina seen by ophtalmoscopy. The patient has
malignant hypertension. - A normal retinal fundus is found in Fig.
6-5.

A necrotic arteriolitis is often found by ophtalmoscopy in malignant
hypertension.

Causative or risk factors for essential
hypertension include genes, because there is a clear racial and familial accumulation of
hypertension. A risk factor is a factor showing statistical covariance with
the disease - see also Chapter 10.

Africans have higher arterial blood pressure than Caucasians, and some
families accumulate cases of hypertension. Specific genes have not been
identified.

The environmental factors are numerous, but Western Hemispher lifestyleis
the key word, since the occurrence of increasing systemic blood pressure with
increasing age is obviously related to accumulation of disease. However,
accumulation of hypertension with age is not a law of nature.

Western lifestyle is sedentary, with psychological stress in career and
family life. Existential procedures have to be performed rapidly including
buying and eating fast food. Persons with a stressful everyday life, with
smoking, alcohol and large meals following long work hours, practice little
exercise if any, and become obese with hyperlipidaemia, hyperglycaemia and
hyperuricaemia.

One essential and measurable variable in the life style pattern is the
lack of exercise (eg, physical inactivity). A low maximum oxygen capacity or fitness
number is measurable with the submaximal exercise test of Åstrand (Fig.
18-3), and reproducible in each individual. The fitness number is expressed as
the maximum oxygen uptake in ml*min-1*kg-1.

A maximum oxygen uptake below 34 (ml*min-1*kg-1)
is related to risk factor accumulation and
early death from hypertensive or other related complications (Fig. 18-14).Such a low maximum uptake is a clear indication of physical inactivity,
where dilatation of muscular arterioles is seldom or almost never achieved.

The unknown cause of essential hypertension in the Western Hemisphere may
well prove to be physical inactivity and the related life style patterns described above.

In some cases of hypertension there is a clear relation to therenin-angiotensin-aldosterone cascade(Chapter 24). The series of events
starts with a rise in TPVR due to
increased vascular tone. Over months and years, the walls of arteries and
arterioles thicken and atherosclerosis is spread in the arterial tree. Such
changes reduce the driving pressure in the renal arteries, which leads to a
fall in glomerular filtration rate (GFR) and increased NaCl/water retention (Chapter
25). The falling pressure in the renal artery triggers b-receptors
on the JG-cellsof the juxtaglomerular apparatus (Fig. 25-17). Renin is released
from these cells located in the afferent glomerular arteriole. Renin separates
the decapeptide, angiotensin I, from the liver globulin, angiotensinogen. When
angiotensin I passes the lungs or the kidneys, a dipeptide is cut off from the
decapeptide by an angiotensin-converting enzyme (ACE). Hereby angiotensin II
(octapeptide) is produced. Angiotensin II stimulates the aldosterone secretion
from the adrenal cortex, and thus stimulates the Na+ reabsorption
and the K+ secretion in the distal, renal tubules. The
renin-angiotensin-aldosterone cascade further contributes to the salt and
water retention. Angiotensin II is also a circulating vasoconstrictor just as
adrenaline and vasopressin found in high plasma concentrations in many
hypertonics. ACE inhibitors (see later) are rational choices for hypertonics
with high angiotensin II, but also for other categories for reasons unknown
(diabetics etc). The cascade is
further described in Chapter 24 – paragraph 6.

There are two forms of hypertension, I) primary or essential, and II)
secondary hypertension.

I) Primary hypertensionis
a multifactorial syndrome without known cause. Approximately 90% of all cases
are classified as primary or essential hypertension, because the causative
factors are not clarified in detail. Increased peripheral resistance is
responsible for most cases of primary hypertension.

In about 10% of all cases the cause of the hypertension is clarified, and
these patients are classified as secondary hypertension.This condition must always be suspected in young hypertonics.

Renal, endocrine or cardiovascular diseases cause secondary hypertension
or it relates to pregnancy or to drugs. Endocrine disorders are treated
systematically in Chapters 26-30.

1.Renal
disorders (Chapter
25)
account for more than 80% of all cases of secondary hypertension. The
disorders are chronic cases of glomerulonephritis, pyelonephritis and other
permanent damage of the kidneys, where salt and water retention dominates.
Hyperparathyroidism and Ca2+ overload can lead to renal
failure and severe hypertension. A renal artery stenosis sufficient to
reduce the glomerular pressure leads to renin release from the juxtaglomerular
apparatus, aldosterone release and thus to increased
salt-water retention (see the renin-angiotensin-aldosterone
cascade, Chapter
24, paragraph 6). Renal artery stenosis (atherosclerosis
or fibromuscular hyperplasia), chronic renal inflammation (glomerulonephritis
or pyelonephritis), and congenital polycystic kidneys can lead to secondary,
systemic hypertension. Renal function is examined with endogenous creatinine
clearance and the renal vessels by scanning or arteriography. The plasma renin
concentration is measured. - Dopamine D3 receptors seem to be
deficient in the development of salt-dependent hypertension (Luipold et al.,
2001).

2.Hyperaldosteronism has a primary and a secondary form. Conn´s syndrome is primary hyperaldosteronism. This condition is characterised by an isolated rise in
serum aldosterone, since the cause is hyperfunction of the zona glomerulosa of
the adrenal cortex - not the renin release. Secondary hyperaldosteronism is a
condition with abnormally high stimulation of the adrenal zona glomerulosa.
The serum concentrations of the whole renin-angiotensin-aldosterone cascade
are increased.

3.Cushing’s
syndrome describes clinical
conditions with increased glucocorticoid concentration in the blood plasma.
The classical Cushings disease is
caused by excess liberation of ACTH
from the adenohypophysis, but ACTH excess is also known to originate from
ectopic ACTH producing tumours or from excess administration of ACTH. -Non-ACTH related adrenal adenomas or carcinomas, glucocorticoid excess
administration, and alcohol abuse (so-called Pseudo-Cushing)
cause Cushing’s syndrome. - The dexamethasone
suppression test is described in Chapter
30.

5.Phaeochromocytoma. This is a tumour of the
sympathetic nervous system (Ch. 28) releasing both noradrenaline and
adrenaline. The signs are intermittent or constant systemic hypertension,
tachycardia with other arrhythmias, orthostatic hypertension and flushing.

6.In the last three
months of pregnancy some females develop hypertension, oedema and proteinuria
(pre-eclampsia or toxaemia of
pregnancy). If this condition develops into severe hypertension with fits
and lung oedema, it is called eclampsia.
This is a life threatening condition, which must be treated immediately with
intravenous hydralazine or minoxidil, and if necessary termination of
pregnancy. Hydralazine is orally active vasodilatators, which work by direct
relaxation of smooth muscles.

7.Drugs such as steroids or oral
contraceptives with high oestrogen, sympatomimetics, aldosterone, and
vasopressin all cause severe systemic hypertension.
Monoamineoxidase-inhibitors combined with tyramine (cheese) or wine sometimes
cause hypertension. A careful medical history is helpful.

8.Cardiovascular
disorder - as coarctation of
the aorta - is the cause of hypertension in a few young patients. The
coarctation produces a late systolic murmur. These hypertonics have a low
pressure distal to the coarctation.

9.Atherosclerosis (see Chapter
10)is characterised by a special systolic hypertension frequently found in
the elderly without any diastolic hypertension. These patients do not have any
arteriolar disease.

Systemic hypertension is a health threat to the person as a whole, since the untreated disease
shortens life expectancy with approximately 20 years. Target organs for damage
are the heart, aorta, brain, eyes and the kidneys.

The positive effect on life expectancy of a moderate reduction of an
abnormally high systemic arterial blood pressure is well documented.

The simple resistance model presented
in Eq. 9-1 is applied for the therapy of systemic hypertension. The driving pressure in the systemic circulation is equal to the cardiac
output multiplied with the Total
Peripheral Vascular Resistance(TPVR).

The cardiac output is equal to the cardiac
frequency multiplied with the stroke
volume, and the stroke volume depends of the total blood volume. TPVR depends
of the degree of contraction of the resistance vessels and of the
distensibility (eg, specific compliance) of the arterial system.

Principally, systemic hypertension is therefore treatable through one or
more of the following strategies:

1. Reduction
of the total blood volume (and thus the stroke volume) with diuretics
results in reduction of the driving pressure,

In healthy individuals, the opening of resistance vessels during exercise
typically reduces the TPVR to 30% of
the value at rest. This vasodilatation expresses an enormous capacity, which
is only present in the resistance vessels of the striated muscular system at
large. The only natural way to break the vicious circle described above is to
maintain the dilatation capacity throughout life by frequent use of the
locomotor system. The exercise must include large muscle groups for some time.
The exercise must be relaxed and comfortable in order to become a life style.
Other beneficial effects of relaxed
duration exercise (such as walking, golf, jogging, swimming, badminton,
tennis etc) is improvedglucose
tolerance, weight loss, improved heart function, improved lipid profile,
normal gastrointestinal functions and psychological benefits such as improved
mood and a healthy sleep pattern. Healthy food and drinking habits are
important, and smoking has to be given up.

Initial administration of diuretics produce a pronounced renal salt and
water excretion, which lead to a reduction in ECV, and a fall in systemic
blood pressure. The urinary salt and water excretion returns to normal after
several days, but the blood pressure remains at the reduced level. This is
difficult to explain. Perhaps some diuretics have a direct relaxing effect on
vascular smooth muscle in the arterioles or other vessels.

b-blockersantagonise competitively the
effects of adrenaline and nor-adrenaline on b-adrenergic vasodilatating receptors. The
typical non-selective b-adrenergic
receptor blocker is propranolol, which is a potent reversible antagonist at
both b1-and b2-adrenergic
receptors. Propranolol acts on the heart and reduces the chronotropic (reduced
heart rate) and inotropic effect (reduced force and cardiac output); the
reduced cardiac function is most pronounced during high sympatho-adrenergic
activity, such as during exercise or stress, so the drug can release acute
cardiac failure. The anti-arrhythmic effect of propranolol is probably due to
its local anaesthetic action on cardiac cells including pacemaker cells. The
effect of propranolol on hypertension is not clarified, since it seems to
increase peripheral vascular resistance slightly. Simultaneously, propranolol
reduces the release of renin from the juxtamedullary apparatus. This inhibits
aldosterone secretion, and thus reduces the potassium secretion of the distal
tubular system. The result is potassium retention, which is further aggravated
by b-blockade of receptors on cell
membranes, whereby the adrenaline-stimulated Na+-K+ pump
is inhibited. Following meals containing carbohydrate and potassium, there is
a release of insulin, which stimulates the Na+ - K+ pump, and thus the K+ uptake in cells. Adrenaline also stimulates
the Na+- K+pump through activation of b2 - receptors, whereby the plasma-[K+] is reduced. The normal effect of insulin is hypoglycaemia, which is
compensated by lipolysis and glycogenolysis (with FFA and glucose liberation),
by increased sympathoadrenergic activity. Propranolol inhibits lipolysis from
adipocytes and glycogenolysis from hepatocytes, myocardial and skeletal muscle
cells. This is a problem with diabetics or for patients with reduced glucose
tolerance. b-blockade
may lead to life threatening hypoglycaemia or a serious rise in blood
pressure, if adrenaline release dominates. Propranolol is thus contraindicated
in persons with diabetes, sinus bradycardia, partial heart block and
congestive heart failure. Propranolol increases airway resistance, which is a
hazard to patients with COLD or asthma, because of bronchoconstriction.

Many b-blockersact selectively, but
all compounds have effects as described below:

Selectiveb1-blockers acts on the cardiac b1-receptors and reduces the force of cardiac contraction and thus lowers
the blood pressure.

Blockade of b1-adrenergic receptors located on the renin-secreting juxtaglomerular
cells reduces the renin release and the blood pressure in persons with
renin-dependent hypertension (eg, patients with a high renin level in the
plasma from renovascular disease).

Many b-blockersreach the brain
tissue through the blood-brain barrier, and others reach the brain cells
through the large fenestrae of the circumventricular organs. The CNS-effect is
an inhibition of the sympatho-adrenergic output, and beneficial effects on
paroxysms of panic and anxiety. The hypotonic CNS-effect is probably
dominating, and explains the maintained lowering of blood pressure, although
the initial reduction in cardiac output is often only temporary.

inhibit the effect mediated through noradrenaline released from
sympathetic presynaptic fibres to the postsynaptic a1-receptors and produce vasodilatation.Also a central effect of these compounds (doxazosin, prazosin) may be
involved. The hypotensive efficiency of these drugs give rise to the main
complication, which is a serious fall in blood pressure following the first
dose.

Angiotensin converting enzyme is found to have the highest activity in the endothelium of the long
pulmonary capillaries. Converting enzyme is a kininase II, which convert the decapeptide, angiotensin I, to the vasoconstrictive
octapeptide, angiotensin II. ACE inhibitors (captopril, enalapril, and
lisinopril) reversibly inhibit converting enzyme and thus act as a vasodilatator of both resistance and capacitance vessels. Angiotensin II is a
potent vasoconstrictor, in particular when its concentration in plasma is
high. Patients with 100 pg l-1 or more of angiotensin II react
beneficial on ACE inhibitors. Also other hypertonics such as diabetic
patients reduce their risk of vascular insults by the use of ACE inhibitors for reasons unknown.

Ca2+-antagonists(amlodipine, nifedipine, diltiazem, and verapamil) acts as effective
vasodilatators, because they relax the smooth muscles of the arterioles. They
also inhibit the cardiac contractile force. Ca2+ -antagonists
inhibits the Ca2+ -entry into the cells, because they bind to the
proteins of Ca2+ -channels in the membrane. The overall effect is
beneficial incongestive heart failure, because the vasodilation dimishes TPVR and thus reduces afterload. Hereby, the cardiac output is improved despite
cardiac contractile depression.

·A
rational strategy is to control the risk factors for the patients. A
successful lowering of arterial blood pressure with a hypotensive drug must
not be accompanied by an unrecognised consequential rise in other risk
factors.

·Relaxed
exercise is an alternative therapeutic strategy to antihypertensive drugs in
many cases of essential hypertension.

·Mild
and relaxed exercise has other beneficial effects, namely a consequential
reduction of most of the known risk factors for atherosclerosis.

·Healthy
food, exercise and drinking habits are important to hypertonics, and smoking
has to be given up.

This is a simple
resistance model for circulating fluid, and the model is applied for
therapeutic strategies.

Fick's first law
of diffusion: The flux (J) of O2 is equal to the diffusion coefficient of oxygen (D is 10-9 m2 s-1) multiplied with the concentration gradient (dC) per distance
unit (dx) through a given area (A). Fick's first law is written:

Eq. 9-2: J = ( - D × dC)×A/dx
(mol per time unit) with a diffusion gradient (dC) through the area A. Notice
that D/dx is a permeability coefficient (m per s).

A male, age 50 years, visits an
ophthalmologist in order to have measured new lenses for myopia and
astigmatism. Ophtalmoscopy reveals irregular vessel diameter, bleeding,
yellow-white spots, and papillary stasis. The patient is advised to see his
general practitioner, which finds a constant arterial blood pressure of
200/110 mmHg (26.66/14.66 kPa). The heart frequency is 85 beats per min and
the cardiac output at rest is normal.

The patient is an office clerk,
and also has a sedentary off- duty life. The patient is a heavy smoker using
40 cigarettes per day. His father had high blood pressure and died from
cerebral infarction at the age of 62 years.

An X-ray of thorax reveals clear
lung fields and left ventricular hypertrophy.

1. What
is the diagnosis?

2. What
is the treatment of choice?

3. What
is the main risk for this patient?

4. What
happens in the lungs and the left ventricle of this patient?

5. Compare
the left ventricular pressure-volume work rate of this patient to that of a
healthy individual. Assume that they are both at rest with a cardiac output of
5 l per min. Assume that the healthy person has a mean arterial pressure of 90
mmHg (12 kPa).

6. Convert
the work rate units used into watts, and explain the development of
ventricular hypertrophy.

A 59-year old office worker is known to have systemic
hypertension. From the initial arterial pressure of 195/115 mmHg, he was
brought down to a stable level of 160/95 mmHg by antihypertensive drugs.
During work the patient suddenly collapses, and he is brought to hospital in
an unconscious state with an arterial blood pressure of 75/45 mmHg. There are
no signs of hemiplegia. Assume that the brain is hypoxic, and that the brain
is producing lactic acid out of 30% of all glucose molecules combusted here.
Among other values the blood glucose concentration is determined to 5 mM, and
the arteriovenous glucose concentration difference increases to 300% of normal
(0.5 mM).The cerebral bloodflow
(CBF) is reduced to 50% of the normal value (650 mlmin-1). The totalproduction
byoxidative phosphorylation is 36
ATP per glucose molecule, and by anaerobic metabolism 2 ATP per glucose
molecule.

1.What is the most likely diagnosis?

2.Calculate the anaerobic and aerobic contribution to brain
metabolism.

3.Calculate the net glucose
flux and the ATP production in a normal brain, and compare the results to
those of the patient.

A female, 66 years of age,
complains of frontal headache. She has been treated for migraine for the last
40 years. The new headache is different from migraine. The doctor measures her
arterial blood pressure to 195/115 mmHg (25.9/15.3 kPa). By ultrasound
screening the length of her left kidney is measured to be half the length of
the right. Renal arteriography reveals a stenosis of the left renal artery.
The stenosis is relieved by balloon dilatation, where a catheter with a
balloon at its tip is inflated at the right site. The success of the treatment
is confirmed over the following weeks, where her blood pressure reach a level
of 145/95 mmHg (19.3/12.6 kPa).

A female, age 22 years, is sitting
on a bicycle ergometer with her calf muscles 0.9 m below heart level.She is at rest and the venous pressure is 10 mmHg (1.3 kPa) at the
level of the heart. The oxygen uptake(VO2) is 0.247 l STPD per min
and the muscle bloodflow is 3 ml per min per 100 g of tissue (3 Flow Units,
FU). The total weight of all her skeletal muscles is 30 kg.

Following 5 min of rest,she starts cycling,hereby
increasing her oxygen uptake to 4.5 l STPD per min, and her muscular
arterioles dilatate to reach a three-fold increase in inner radius. During
exercise the arterio-venous O2 content difference is 170 ml STPD
per l, and the oxygen uptake in the skeletal muscles increases from 1 to 100
ml STPD per min per kg.

1.Calculate the venous pressure in the calf muscles at rest.

2.Calculate the relative alteration of the muscular vascular resistance
during exercise.

3.Calculate the driving blood pressure over the working muscles during
exercise, where the arterial blood pressure is 170/70 mmHg (22.7/9.3 kPa) and
the venous pressure in the calf muscles is reduced to 20 mmHg (2.6 kPa).

·The
cardiac output(Q) is the stroke volume multiplied by the cardiac frequency.
The heart must pump harder to provide a given Q°with
increasing age, because the arteries become increasingly stiff with age.

·The
distensibility or compliance of the arterial system diminishes with age due to
atherosclerosis.

·When
the pressure wave travels through the arterial tree, the arterial compliance
is always less in the distal part of the system.

·The
mean arterial pressure (MAP) is a good estimate of the driving pressure (DP),
whereas the pulse pressure varies almost directly with the stroke volume.

·MAP
and Q are easy to determine, allowing a calculation oftotal peripheral vascular resistance (TPVR). The systemic TPVR is one
PRU at rest and 0.3 PRU during exercise.

·The
velocity of the systemic arterial pressure wave varies inversely with the
arterial compliance, whereby the velocity increases with age and with
increasing degrees ofhypertension.

·The
high frequency components of the systemic arterial pressure wave are damped in
the periphery, and the systolic peak components are elevated.

·The
MAP varies directly with the Q and the TPVR.. The resistance model for
circulating blood: DP
= Q°*
TPVR is applicable for therapeutic strategies in hypertension.

·The
EEG of an anoxic brain is recognisable as a straight EEG trace (no electrical
activity) indicating brain death. Because [Ca2+] rises in the nerve
cell, this increases the K+ conductance, so that more K+ leaks out into the ISF.

·The
arterial blood pressure is measured indirectly in the brachial artery with
Korotkoff´s auscultatory method (standardised by WHO). The systolic pressure
is recorded by the occurrence of a tapping sound, and the diastolic pressure
is manifested by the disappearance of the sound.

·Populations
living under natural conditions - including Indian troops in Brazil and
healthy living persons in the Western Hemisphere - maintain their mean
arterial pressure (MAP) throughout life.

·In
the rich part of the World, the MAP and the systolic pressure, measured as an
average for the total population, increases with increasing age.

·Systemic
hypertension- according to WHO - is defined as an arterial blood pressure
exceeding 160/95 mmHg (21.3/12.6 kPa) for several months. The pressure
increase is either systolic, diastolic or a combination.

·Systemic
hypertension is the most frequently diagnosed and treated risk factor for the
development of atherosclerosis including ischaemic heart disease.

·The
cause of essential hypertension in the western world may well prove to be
physical inactivity and related life style patterns.